Forty Percent Methionine Restriction Decreases Mitochondrial Oxygen Radical Production and Leak at Complex I During Forward Electron Flow and Lowers Oxidative Damage to Proteins and Mitochondrial DNA in Rat Kidney and Brain Mitochondria

Abstract

Eighty percent dietary methionine restriction (MetR) in rodents (without calorie restriction), like dietary restriction (DR), increases maximum longevity and strongly decreases mitochondrial reactive oxygen species (ROS) production and oxidative stress. Eighty percent MetR also lowers the degree of membrane fatty acid unsaturation in rat liver. Mitochondrial ROS generation and the degree of fatty acid unsaturation are the only two known factors linking oxidative stress with longevity in vertebrates. However, it is unknown whether 40% MetR, the relevant methionine restriction degree to clarify the mechanisms of action of standard (40%) DR can reproduce these effects in mitochondria from vital tissues of strong relevance for aging. Here we study the effect of 40% MetR on ROS production and oxidative stress in rat brain and kidney mitochondria. Male Wistar rats were fed during 7 weeks semipurified diets differing only in their methionine content: control or 40% MetR diets. It was found that 40% MetR decreases mitochondrial ROS production and percent free radical leak (by 62-71%) at complex I during forward (but not during reverse) electron flow in both brain and kidney mitochondria, increases the oxidative phosphorylation capacity of brain mitochondria, lowers oxidative damage to kidney mitochondrial DNA, and decreases specific markers of mitochondrial protein oxidation, lipoxidation, and glycoxidation in both tissues. Forty percent MetR also decreased the amount of respiratory complexes I, III, and IV and apoptosis-inducing factor (AIF) in brain mitochondria and complex IV in kidney mitochondria, without changing the degree of mitochondrial membrane fatty acid unsaturation. Forty percent MetR, differing from 80% MetR, did not inhibit the increase in rat body weight. These changes are very similar to the ones previously found during dietary and protein restriction in rats. We conclude that methionine is the only dietary factor responsible for the decrease in mitochondrial ROS production and oxidative stress, and likely for part of the longevity extension effect, occurring in DR.

An evolutionary comparative scan for longevity-related oxidative stress resistance mechanisms in homeotherms

“…With reference to the effect of MetR on mtROS generation and oxidative stress, it have been found that 80% MetR (without CR), as well as 40% MetR (Caro et al 2008(Caro et al , 2009, also decreases mtROS generation (mainly at complex I), % free radical leak, mtDNA oxidation, complex I content, specific markers of protein oxidative modification, and membrane unsaturation, in rat heart and liver mitochondria (Sanz et al 2006a, b, c, d), as well as rat kidney and brain mitochondria (Caro et al 2008(Caro et al , 2009, and that these decreases were dose-dependent and stronger at 80% than 40% MetR (Sanz et al 2006a, b, c, d;Caro et al 2008Caro et al , 2009. Strikingly, the pattern of many of these changes was very similar to those previously found in CR and PR.…”

Regulation of Membrane Unsaturation as Antioxidant Adaptive Mechanism in Long-lived Animal Species

“…[71][72][73] Thus, a decrease in membrane unsaturation, lipid peroxidation and lipoxidation-derived damage has been reported in tissues (liver, heart, and brain) from these dietary restrictions in rats and mice. [74][75][76][77][78][79][80][81][82][83][84] CR has also been shown to reduce levels of lipofuscin in tissues of rodents and C. elegans. [62,[85][86][87][88] From these studies it can be inferred that the magnitude of the change is modest for membrane unsaturation (between 2.5-10%) than that for the lipoxidation-derived molecular damage (between 20-40%) likely due to the added effect of the lower mitochondrial free radical generation also induced by these nutritional interventions.…”

Resveratrol reduces lipid peroxidation and increases sirtuin 1 expression in adult animals programed by neonatal protein restriction

“…The dietary factor that may be responsible for part of the longevity extension effect occurring in chronic ER is the restriction of the specific amino acid methionine. Studies have shown that methionine restriction can decrease mitochondrial ROS production and oxidative stress (Caro et al 2009a). Restriction of dietary amino acids other than methionine decreases mitochondrial protein oxidation and increases SIRT1 in rat liver (Caro et al 2009b).…”